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Whole genome reverse genetic screen for natural deleterious variants in 4000 domestic ruminants to gain insight into mammalian gene function
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International audience. In recent decades, the study of laboratory mammalian models (such as knock-out rodents) has dramatically improved our knowledge of the molecular basis of many phenotypes. However, this approach has several limitations. As an alternative, we propose to study natural genetic variation in ruminants (cattle, sheep and goats) as a complementary source of information to gain new insights into the function of genes in mammals and their pathological consequences of their inactivation. Using a reverse genetic approach, we aggregated whole-genome sequencing data from 2500 cattle, 1400 goats and 100 sheep to generate a catalog of putative loss-of-function (frameshift, stop-gained and essential splice) and deleterious missense (SIFT score <0.05) variants located in 1:1 pairwise protein-coding genes orthologous to humans (16,409 genes). In this study, we particularly focused on nuclear genes encoding mitochondrial proteins and estimated the effects of this subset of variants on the performance and life trajectories of animals routinely genotyped for genomic evaluation. Phenotypic description and functional validation of the most promising variants are currently ongoing. The study of natural variants in livestock, especially those located in genes poorly characterized in mammals, could provide valuable information on the molecular mechanisms that determine phenotypic variation.
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